Fluoroalkylation Methods And Reagents

ABSTRACT

A method of forming a fluorinated molecular entity includes reacting in a reaction mixture an aromatic halide, copper, a fluoroalkyl group, and a ligand. The aromatic halide includes an aromatic group and a halogen substituent bonded to the aromatic group. The ligand includes at least one group-V donor selected from phosphorus and an amine. The overall molar ratio of copper to aromatic halide in the reaction mixture is from 0.2 to 3. The method further includes forming a fluoroalkylarene including the aromatic group and the fluoroalkyl group bonded to the aromatic group. A composition, which may be used in the method, consists essentially of copper, the fluoroalkyl group, and the ligand, where the molar ratio of copper to the fluoroalkyl group is approximately 1.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT Application No.PCT/US2011/048378 entitled “Fluoroalkylation Methods And Reagents” filedAug. 19, 2011, which claims the benefit of U.S. Provisional ApplicationNo. 61/375,396 entitled “Fluoroalkylation Methods And Reagents” filedAug. 20, 2010, each of which is incorporated by reference in itsentirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Contract NumberGM-58108 awarded by the National Institutes of Health. The Governmenthas certain rights in the invention.

BACKGROUND

Fluoroalkyl substituents have become increasingly important in theresearch and development of biologically active compounds includingpharmaceuticals. A number of existing blockbuster pharmaceuticalsinclude a fluoroalkyl substituent. Incorporation of a trifluoromethylgroup into an organic molecule can favorably change its lipophilicityand pharmacokinetics. In addition, investigations of an analogue of acompound in which a methyl group has been replaced by a trifluoromethylgroup can provide insights into the biological activity of the compound.

Although the effect of the trifluoromethyl substituent on biologicalactivity and pharmacokinetics has been studied, methods to incorporatethe trifluoromethyl group into aromatic compounds are limited.Conventionally, aryl compounds have been substituted withtrifluoromethyl groups through the reaction of aryl carboxylic acidswith SF4, or through the fluorination of a trichloromethyl substituentof an aryl compound with Swart's reagent (SbF3). The SF4 and SbF3reagents, however, are toxic and difficult to handle.

In another approach, trifluoromethyl groups have been incorporated intoaromatic compounds using palladium-mediated or palladium-catalyzedreactions. Each of these approaches, however, has at least onedisadvantage, such as limited toleration of functionality, high loadingsof an expensive phosphine ligand, high loadings of palladium, hightemperature conditions, or the need for an expensive CF₃ source.

In yet another approach, trifluoromethyl groups have been incorporatedinto aromatic compounds using copper(I) reagents and catalysts. Thesereactions, however, also have severe limitations for syntheticapplications. Reactions of a trifluoromethylcopper complex prepared fromCuX and either Cd(CF₃)X or Zn(CF₃)X have been reported, as havereactions using CuI and trialkyl(trifluoromethyl)silanes with KF as anactivator. These methods, however, involve toxic cadmium reagents andHMPA solvent to facilitate formation of CuCF₃, and/or occur with limitedfunctional group compatibility and in poor yields with electron-richaryl halides. Trifluoromethylcopper compounds ligated by N-heterocycliccarbenes (NHC) are not useful for preparative work because the compoundsare prepared by a three-step synthesis starting with an expensive NHCligand. Trifluoromethylation catalyzed by copper iodide using methylfluorosulfonyldifluoroacetate FSO₂CF₂CO₂Me as the source of CF₃generates toxic SO₂ and MeI and cannot be extended to higherperfluoroalkyl groups. Trifluoromethylation of aryl iodides with acatalytic amount of copper iodide ligated by 1,10-phenanthrolinerequires the expensive TESCF₃ reagent, and high yields were obtainedonly with electron-deficient aromatic halides.

Accordingly, it would be desirable to form fluoroalkylarenes under mildconditions in a manner that would tolerate a wide variety of functionalgroups. Preferably such a fluoroalkylation method would utilize reagentsthat are readily accessible, relatively inexpensive, and less toxic thanconventional fluoroalkylation reagents.

SUMMARY

In one aspect, the invention provides a method of forming a fluorinatedmolecular entity that includes reacting in a reaction mixture anaromatic halide, copper, a fluoroalkyl group, and a ligand. The aromatichalide includes an aromatic group and a halogen substituent bonded tothe aromatic group. The ligand includes at least one group-V donorselected from phosphorus and nitrogen. The overall molar ratio of copperto aromatic halide in the reaction mixture is from 0.2 to 3. The methodfurther includes forming a fluoroalkylarene including the aromatic groupand the fluoroalkyl group bonded to the aromatic group.

In another aspect of the invention, there is a composition consistingessentially of copper, a fluoroalkyl group, and a ligand including atleast one group-V donor. The molar ratio of copper to the fluoroalkylgroup is approximately 1.

In another aspect of the invention, there is a composition consistingessentially of copper, a fluoroalkyl group, a first ligand including atleast one group-V donor, and a second ligand, different from the firstligand. The molar ratio of copper to the fluoroalkyl group isapproximately 1.

In another aspect of the invention, there is a method of forming afluorinated molecular entity that includes reacting in a reactionmixture a vinyl halide, copper, a fluoroalkyl group, and a ligand. Thevinyl halide includes an organic group containing a vinyl group and ahalogen substituent bonded to a carbon of the vinyl group. The ligandincludes at least one group-V donor selected from phosphorus andnitrogen. The overall molar ratio of copper to vinyl halide in thereaction mixture is from 0.2 to 3. The method further includes forming afluoroalkylvinyl compound including the organic group containing a vinylgroup, and the fluoroalkyl group bonded to a carbon of the vinyl group.

In another aspect of the invention, there is a method of forming acopper-containing reagent that includes reacting in a reaction mixture acopper source, an alcohol, a compound including at least one group-Vdonor, and a tri-organo(fluoroalkylsilane). The copper source includes acopper-carbon bond or a copper-nitrogen bond. The method furtherincludes forming [(L)Cu—R_(f)] in the reaction mixture; where L is aligand comprising at least one group-V donor, and R_(f) is a fluoroalkylgroup.

To provide a clear and more consistent understanding of thespecification and claims of this application, the following definitionsare provided.

The term “molecular entity” means any constitutionally or isotopicallydistinct atom, molecule, ion, ion pair, radical, radical ion, complex,conformer etc., identifiable as a separately distinguishable entity.

The term “group” means a linked collection of atoms or a single atomwithin a molecular entity. The description of a group as being “formedby” a particular chemical transformation does not imply that thischemical transformation is involved in making the molecular entity thatincludes the group.

The term “chemical transformation” means the conversion of a substanceinto a product, irrespective of reagents or mechanisms involved.

The term “aromatic halide” means a molecular entity containing anaromatic group having a halide substituent (F, Cl, Br, I) bonded to thearomatic group.

The term “aromatic group” means a cyclic group containing an aryl groupand/or a heteroaryl group. An aromatic group may be monocyclic orpolycyclic and may include one or more substituent groups.

The term “aryl group” means a group formed by removing a hydrogen from aring carbon atom of an aromatic hydrocarbon. An aryl group may bemonocyclic or polycyclic and may include one or more substituent groups.

The term “heteroaryl group” means a group formed by replacing one ormore methine (—C═) and/or vinylene (—CH═CH—) groups in an aryl groupwith a trivalent or divalent heteroatom, respectively. A heteroarylgroup may be monocyclic or polycyclic and may include one or moresubstituent groups.

The term “substituent” means a group that replaces one or more hydrogenatoms in a molecular entity. Examples of substituents include halidegroups, alkyl groups, heteroalkyl groups, aryl groups, and heteroarylgroups. A heteroalkyl or heteroaryl substituent may be bonded to theremainder of the molecular entity through a carbon or through aheteroatom.

The term “alkyl group” means a group formed by removing a hydrogen froma carbon of an alkane, where an alkane is an acyclic or cyclic compoundconsisting entirely of hydrogen atoms and saturated carbon atoms. Analkyl group may be substituted with one or more substituent groups.

The term “fluoroalkyl group” means an alkyl group substituted with oneor more fluoride groups.

The term “ligand”, when referring to a distinct substance, means anorganic compound that can be associated to a metal atom when combinedwith the metal atom.

The term “group-V donor” means an atom from group-V of the periodictable (N, P, As, Sb), where the group-V atom is a Lewis base.

The term “group-VI donor” means an atom from group-VI of the periodictable (O, S, Se), where the group-VI atom is a Lewis base.

The term “heterocyclic group” means a group formed by removing ahydrogen from a carbon of a heterocycle, where a heterocycle is a cycliccompound consisting of hydrogen atoms, carbon atoms, and one or moreheteroatoms. A heterocyclic group may include one or more substituentgroups. Heterocyclic groups include cyclic heteroalkyl groups, cyclicheteroalkenyl groups, cyclic heteroalkynyl groups and heteroaryl groups.

The term “overall molar ratio” means the molar ratio of the totalamounts of two reactants in a reaction mixture over the course of areaction, which begins with the combination of at least a portion of thetwo reactants and ends when the yield of the product of the reaction isno longer increasing.

The term “fluoroalkylarene” means a molecular entity containing anaromatic group and a fluoroalkyl substituent bonded to the aromaticgroup.

The term “fluoroalkylvinyl compound” means a molecular entity containingan organic group that includes a vinyl group, and a fluoroalkylsubstituent bonded to a carbon of the vinyl group.

The term “functional group” means a group that includes atoms other thanhydrogen and spa carbon atoms, and that has similar chemical propertieswhen it occurs in different organic compounds. Examples of functionalgroups include hydroxyl (—OH), protected hydroxyl, ether (—C—O—C—),ketone (>C═O), ester (—C(═O)O—C—), carboxylic acid (—C(═O)OH), cyano(—C≡N), amido (—C(═O)NH—C—), protected amino, thiol (—SH), sulfone,sulfoxide, phosphine, phosphite, phosphate, and halide (—X).

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdrawings and description. The components in the figures are notnecessarily to scale and are not intended to accurately representmolecules or their interactions, emphasis instead being placed uponillustrating the principles of the invention. Moreover, in the figures,like referenced numerals designate corresponding parts throughout thedifferent views.

FIG. 1 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides.

FIG. 2 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides, wherethe aromatic iodide was used as the limiting reactant.

FIG. 3 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides, wherethe copper, ligand and fluoroalkyl source were added to the reactionmixture as separate ingredients, rather than as a 1-component reagent.

FIG. 4 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides, wherethe fluoroalkyl group was a perfluoropropyl group.

FIG. 5 depicts chemical structures, a reaction scheme and a productyield for a mechanistic study of a fluoroalkylation reaction.

FIG. 6 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic bromides.

DETAILED DESCRIPTION

Fluoroalkylation may be performed with a range of organic halides byreacting an organic halide in a reaction mixture containing copper, afluoroalkyl group, and an inexpensive ligand, where the overall molarratio of copper to organic halide in the reaction mixture is from 0.2 to3. The fluoroalkylation reaction may be carried out at room temperature,and may be effective with aromatic halides having substituents that areelectron-donating, neutral or electron-withdrawing. A variety offluoroalkyl groups can be used to replace the halide on the organicgroup.

Moreover, a composition containing the copper, the fluoroalkyl group andthe ligand can serve as a shelf-stable, one-component reagent for thefluoroalkylation reaction. The reagent may be prepared from relativelyinexpensive components, and may be stored at ambient temperature under anitrogen atmosphere. The reagent may be used in a reaction mixture toprovide fluoroalkylation of a range of organic halides.

A method of forming a fluorinated molecular entity includes reacting ina reaction mixture an aromatic halide, copper, a fluoroalkyl group and aligand, and forming a fluoroalkylarene in the reaction mixture. Thearomatic halide includes an aromatic group and a halogen substituentbonded to the aromatic group. The ligand includes at least one group-Vdonor. The overall molar ratio of copper to aromatic halide in thereaction mixture is from 0.5 to 3. The fluoroalkylarene formed in thereaction mixture includes the aromatic group and the fluoroalkyl groupbonded to the aromatic group.

The aromatic halide includes an aromatic group and a halogen substituentbonded to the aromatic group. The halogen substituent preferably isbromine (—Br) or iodine (—I). The aromatic group may be an aryl group,and preferably may be any C6-C20 aryl group. Examples of aryl groupsinclude a phenyl group, a biphenyl group and a binaphthyl group. Thearomatic group may be a heteroaryl group, and preferably may be anyC3-C20 heteroaryl group. Examples of heteroaryl groups include a pyridylgroup, a quinoline group, a pyrimidine group and an indole group. Thearomatic group may further include other substituents, such as an alkylgroup, an ether group, a hydroxyl group, an aldehyde group, a ketonegroup, an ester group, an amine group, an amide group, a cyano group, anitro group, a bromide group, and a chloride group. The aromatic halidemay be electron-neutral, electron-rich or electron-deficient.

The copper preferably is present in the reaction mixture as copper(I).The copper may be present in the reaction mixture in any of a variety offorms, including an ion, a salt, a complex or a compound. The copper maybe added to the reaction mixture as a complex with the fluoroalkyl groupand/or the ligand. The copper may be added to the reaction mixture as ahalide, such as copper(I) chloride (CuCl), copper(I) bromide (CuBr) orcopper(I) iodide (CuI). The copper may be added to the reaction mixtureas an oxide, such as copper(I) oxide (Cu₂O). The copper may be added tothe reaction mixture as a complex with one or more alkoxy ligands, suchas copper(I) t-butoxide [Cu—O-t-Butyl]4. The copper may be added to thereaction mixture as a complex with one or more other ligands, such ascopper(I) triflate or copper(I) thiocyanate.

The fluoroalkyl group preferably has the formula —C_(x)H_((2x-y))F_(y),where x is from 1 to 12 and y is from 1 to (2x+1). Preferred fluoroalkylgroups include —CF₃, —CF₂CF₃, —CH₂CF₃, —CH₂CH₂F, —CF₂CF₂CF₃, —CH₂CF₂CF₃,—CH₂CH₂CF₃, —CH₂CH₂CH₂F, —CH(CF₃)₂ and —CF(CF₃)₂. The fluoroalkyl groupmay be added to the reaction mixture as part of a complex with thecopper. The fluoroalkyl group may be added to the reaction mixture aspart of a silane compound, such as a tri-organo(fluoroalkylsilane).Examples of tri-organo(fluoroalkylsilanes) includetrimethyl(fluoroalkylsilanes), triethyl(fluoroalkylsilanes),dimethylphenyl(fluoroalkylsilanes),tert-butyl-dimethyl(fluoroalkylsilanes),triisopropyl(fluoroalkylsilanes), trifluoromethyl(fluoroalkylsilanes),triphenylsilyl(fluoroalkylsilanes), tri-organo(perfluoroethylsilanes),tri-organo-(perfluoropropylsilanes), and tri-organo(fluoroalkylsilanes)in which the fluoroalkyl group is partially fluorinated. For example,the fluoroalkyl group may be added as a trimethyl(fluoroalkylsilane)(TMS-R_(f), where TMS denotes the trimethylsilyl group, and R_(f)denotes the fluoroalkyl group). Specific examples of atrimethyl(fluoroalkylsilane) include trimethyl(trifluoromethylsilane)(TMS-CF₃, Ruppert's reagent). The fluoroalkyl group may be added to thereaction mixture as trifluoroacetic acid or methylfluorosulfonyldifluoroacetate.

The ligand includes at least one group-V donor. Preferably the ligandincludes at least one group-V atom such as phosphorus or nitrogen. Morepreferably the ligand includes at least one group-V atom selected fromthe group consisting of phosphorus, a ring nitrogen of a heterocyclicgroup, and an amine. The ligand may be added to the reaction mixture aspart of a complex with the copper. The ligand may be added to thereaction mixture as a free compound, or it may be added as part ofanother substance, such as a salt of the ligand with an ion or a complexof the ligand with another metal.

Examples of ligands that include at least one phosphorus atom, a ringnitrogen of a heterocyclic group, or an amine include a phenanthroline,an N,N′-disubstituted diamine, a bipyridyl, a pyridyl, a phosphine, anda phosphite. Each of these ligands may include one or more substituentgroups. For ligands that include a ring structure, one or more ringcarbons may be replaced with a heteroatom. Specific examples of ligandsthat include at least one phosphorus atom include phosphines such astributyl phosphine [(n-Bu)₃P] and triphenyl phosphine (Ph₃P). Specificexamples of ligands that include at least one phosphorus atom includephosphites such as trimethyl phosphite [(MeO)₃P] and triphenyl phosphite[(PhO)₃P]. Specific examples of ligands that include a ring nitrogen ofa heterocyclic group include 1,10-phenanthroline (phen), bipyridyl(bipy) and pyridyl (Py). Specific examples of ligands that include asecondary amine include N,N′-dimethylethylenediamine (DMEDA) andN,N′-dimethyl-cyclohexanediamine (DMECA). Specific examples of ligandsthat include a primary amine include tetramethylenediamine (TMEDA). Theligand also may include substituted derivatives of these examples. Aligand having two or more group-V donor atoms may be present in a molarratio with the copper of approximately 1. A ligand having only onegroup-V donor atom may be present in a molar ratio with the copper ofapproximately 1 to 2.

The reaction mixture preferably includes a solvent, which preferably isa polar, aprotic solvent. Examples of polar, aprotic solvents includeDMF, DMSO, THF and CH₂Cl₂. Preferably the reaction mixture includes DMFas a solvent.

The reaction mixture includes the copper and the aromatic halide at anoverall molar ratio of from 0.2 to 3. This overall molar ratio is themolar ratio of the total amounts of copper and of the aromatic halide inthe reaction mixture over the course of the reaction, which begins withthe combination of at least a portion of the copper and of the aromatichalide, and ends when the yield of the fluoroalkylarene product is nolonger increasing. Preferably the reaction mixture includes the copperand the aromatic halide at an overall molar ratio of from 0.5 to 2.5.More preferably the reaction mixture includes the copper and thearomatic halide at an overall molar ratio of from 0.8 to 2, morepreferably from 0.9 to 1.5, and more preferably from 0.95 to 1.1. Morepreferably the copper is present in a stoichiometric amount relative tothe aromatic halide over the course of the reaction.

The reaction mixture preferably includes the copper and the fluoroalkylgroup at an overall molar ratio of from 0.5 to 3. This overall molarratio is the molar ratio of the total amounts of copper and of thefluoroalkyl group in the reaction mixture over the course of thereaction, which begins with the combination of at least a portion of thecopper and of the fluoroalkyl group, and ends when the yield of thefluoroalkylarene product is no longer increasing. Preferably thereaction mixture includes the copper and the fluoroalkyl group at anoverall molar ratio of from 0.7 to 2.5. More preferably the reactionmixture includes the copper and the fluoroalkyl group at an overallmolar ratio of from 0.8 to 2, more preferably from 0.9 to 1.5, and morepreferably from 0.95 to 1.1. More preferably the copper is present in astoichiometric amount relative to the fluoroalkyl group over the courseof the reaction.

The copper, the ligand and the fluoroalkyl group may form a complex inthe reaction mixture. If the ligand includes one or two group-V donors,the complex may be described with an empirical formula of (L)Cu—R_(f),where L is the ligand and R_(f) is the fluoroalkyl group. If the ligandincludes only one group-V donor, the complex may be described with anempirical formula of (L′)₂Cu—R_(f), where L′ is the ligand and R_(f) isthe fluoroalkyl group. In each of these empirical formulas, the copperis present in a stoichiometric amount relative to the fluoroalkyl group.

In one example, a reaction mixture may be formed by combining in asolvent [Cu—O-t-Butyl]₄ as the copper source, 1,10-phenanthroline as theligand, and either TMS-CF₃ or TMS-CF₂CF₂CF₃ as the fluoroalkyl groupsource, as shown in Scheme 1 below:

Complex 1 in Scheme 1 includes a trifluoromethyl group as thefluoroalkyl group, and complex 2 in Scheme 1 includes a perfluoropropylgroup as the fluoroalkyl group.

In another example, a reaction mixture may be formed by combining asolvent with a copper-containing reagent such as [(phen)Cu—R_(f)]. Thecopper-containing reagent [(phen)Cu—R_(f)] may be formed as shown inScheme 2 below:

Complex 1 and complex 2 are as shown in Scheme 1. Complex 3 in Scheme 2includes a perfluoroethyl group as the fluoroalkyl group.

When present in the reaction mixture, a portion of the copper atoms maybe in the form of a complex with both the ligand and the fluoroalkylgroup, and a portion of the copper atoms may be in the form of a complexwith either the ligand or the fluoroalkyl group. Without being bound byany theory of operation, one possible form of such a copper complex isan ionic double salt of L₂Cu and Cu—(R_(f))₂. In the example of complex1 in Schemes 1 and 2, such a double salt may be denoted as[(phen)₂Cu][Cu(CF₃)₂]. Solution conductivity and ¹⁹F NMR measurements inDMF-d₇ of a combination in DMF of copper, 1,10-phenanthroline andTMS-CF₃ in a 1:1:1 molar ratio are described in Example 2 below. Theseresults were consistent with the presence of both the[(phen)₂Cu][Cu(CF₃)₂] double salt and the (phen)Cu—CF₃ complex.

Thus, a substance represented in the present application as havingformula (L)Cu—R_(f) may be present in a reaction mixture as acombination of (L)Cu—R_(f) and [(L)₂Cu][Cu(CF₃)₂]. Other combinations ofthe ligand, copper and the fluoroalkyl group also may be present in thereaction mixture. In addition, one of the components may be present inexcess of a 1:1 ratio with the other components.

The fluoroalkylarene formed in the reaction mixture includes thearomatic group of the aromatic halide, and the fluoroalkyl group bondedto the aromatic group. Preferably the fluoroalkylarene is formed in ayield of at least 50%. More preferably the fluoroalkylarene is formed ina yield of at least 60%, more preferably of at least 70%, morepreferably of at least 80%, and more preferably of at least 90%.Preferably these yields can be obtained by maintaining the reactionmixture at a temperature of from 25° C. to 80° C. for a period of from 6to 30 hours. More preferably these yields can be obtained by maintainingthe reaction mixture at a temperature of from 25° C. to 50° C. for aperiod of from 12 to 24 hours. More preferably these yields can beobtained by maintaining the reaction mixture at a temperature of fromapproximately 25° C. for a period of approximately 18 hours.

FIG. 1 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides. Reagent1 included an approximately 1:1:1 molar ratio of copper,1,10-phenanthroline ligand and trifluoromethyl group. Reagent 1 was thelimiting reactant, and the reaction mixture had an overall molar ratioof copper to aromatic iodide of 0.2. The reaction of reagent 1 with arange of electron-neutral, electron-rich and electron-deficient aromaticiodides 3 gave trifluoromethylarenes 4 in good yields, which is reportedin FIG. 1 as a percentage of the theoretical yield based on theequivalents of reagent 1. Yields were determined by ¹⁹F NMR analysisusing 4-CF₃OC₆H₄OMe as internal standard, and reported as an average oftwo runs. For the yield identified with the superscript b, the resultwas obtained with reagent 1 that had been stored for over one month. Thereactions occurred with aromatic iodides 3a-3p that contained a widerange of functional groups including amino, alkoxy, hydroxyalkyl, halo,keto, formyl, cyano and nitro groups. The letter designations for thearomatic iodides 3 correlate with the letter designations of thecorresponding trifluoromethylarenes 4.

The synthetic results depicted in FIG. 1 were unexpected and surprisingin view of conventional fluoroalkylation methods. In an example ofunexpected and surprising results, the reactions of reagent 1 with aryliodides containing alcohol, ketone or aldehyde functionalities (3f, 3gand 3h) provided the corresponding trifluoromethyl arenes in yields of75%, 87% and 92%, respectively. In contrast, substrates containingalcohol, ketone or aldehyde functional groups typically do not toleratethe different palladium-catalyzed trifluoromethylation protocols.Moreover, the stability of the carbonyl groups on 3g and 3h towardreagent 1 contrasts with the reaction of these functional groups withCF₃ anions generated from the conventional treatment of Ruppert'sreagent in the presence of fluoride activators.

In another example of unexpected and surprising results, bromoarene 3eand chloroarene 3m reacted selectively at the iodide. In yet anotherexample of unexpected and surprising results, reaction of reagent 1 evenoccurred with 2,6-disubstituted aryl iodides 3n and 3o in good yield.The reactions of reagent 1 were more than ten times faster than thetrifluoromethylation reactions reported using [(SIMes)₂Cu][Cu(CF₃)₂].

FIG. 2 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides, wherethe aromatic iodide was used as the limiting reactant. In syntheticapplications involving a multi-step sequence including thefluoroalkylation, the aromatic iodide would likely be one of the morevaluable components. Thus, conditions similar to those of FIG. 2 may beused in the practical applications of this method. The reactionsdepicted in FIG. 2 were performed using 1.5 equiv of reagent 1 at 50° C.unless otherwise noted. For the reactions identified with thesuperscript b, the yield was determined by ¹⁹F NMR analysis using4-CF₃₀C₆H₄OMe as internal standard. For the reactions identified withthe superscript c, the reaction was performed with reagent 1 that wasweighed in air. For the reactions identified with the superscript d, thereaction was performed at room temperature. For the reactions identifiedwith the superscript e, 1.2 equivalents of reagent 1 were used at roomtemperature. For the reactions identified with the superscript f, 3.0equivalents of reagent 1 were used. The letter designations for thearomatic iodides 3 correlate with the letter designations of thecorresponding trifluoromethylarenes 4.

Referring to FIG. 2, simple and functionalized aromatic iodides againreacted in good yield under these conditions. Reactions of aryl iodides3c and 3g occurred in similar yield to those with the copper complex aslimiting reagent. Simple aryl iodides like 3q and 3r; functionalizedaryl iodides containing amide (3s), ester (3t and 3u), aldehyde (3u) andbromide (3v) functionality; and heteroaryl iodides (3w, 3×, 3y) reactedwith reagent 1 to give trifluoromethylarenes 4 in good isolated yields.The functionalized aryl iodide 3z, available via metalation withKnochel's LiCl-(TMP)MgX reagent, also gave product 4z in good yield.Several heteroaromatic iodides also reacted, including quinoline 3xcontaining an exposed basic nitrogen. Trifluoromethylation of the3,3′-diiodo-BINOL derivative 3aa gave the MOM-protected3,3′-(CF₃)₂-BINOL 4aa under mild conditions. Surprisingly, it was notnecessary to use a glovebox to conduct these reactions. For example, thereaction of p-phenyl iodoarene 3q with reagent 1 that was weighedquickly in air formed the trifluoromethylarene product in 92% yield.

FIG. 3 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides, wherethe copper, fluoroalkyl source and ligand were added to the reactionmixture as separate ingredients, rather than as a 1-component reagent.Thus, a copper complex was formed in situ. Copper chloride, potassiumtert-butoxide and 1,10-phenanthroline were weighed outside the glove boxand then combined in DMF. The mixture was stirred under a nitrogenatmosphere for 0.5 h, and then Ruppert's reagent was added to themixture, providing a molar ratio of copper to fluoroalkyl group (CF₃) toligand of 1:1:1. Subsequent addition of aromatic iodides 3 to themixture provided trifluoromethylarenes 4 in 83 to 99% yield. The letterdesignations for the aromatic iodides 3 correlate with the letterdesignations of the corresponding trifluoromethylarenes 4.

The reactions depicted in FIG. 3 were performed at 0.50 mmol scalewithout the aid of glove box during the preparation of the reactionmixture unless otherwise noted. For the reaction identified with thesuperscript b, the result was obtained in a glove box using a molarratio of copper to aromatic iodide of 1.5. For the reaction identifiedwith the superscript c, the result was obtained at 10 mmol scale for 24hours. For the reactions identified with the superscript d, the yieldwas determined by ¹⁹F NMR analysis using 4-CF₃₀C₆H₄OMe as internalstandard.

Referring to FIG. 3, a selection of fluoroalkylation reactions wereconducted where the copper, fluoroalkyl source and ligand were added tothe reaction mixture as separate ingredients, forming a copper complexin situ. The reactions were performed with aromatic halides containingelectron-donating groups, electron-withdrawing groups, potentiallyreactive functional groups and both electron-rich and electron-poorheterocyclic compounds. The trifluoromethylarenes 4 were produced inyields that were comparable to those observed when the same iodoareneswere reacted with reagent 1.

The addition of the copper, fluoroalkyl group source, and ligand asseparate ingredients may provide advantages when performing thefluoroalkylation reactions on a larger scale. The ability to scale-upthe fluoroalkylation reaction was demonstrated by the reaction ofbenzyloxy-substituted 3r on a 10 mmol scale, which provided 2.5 g of thetrifluoromethylarene 4r after 24 h, which was a 95% yield.

FIG. 4 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic iodides, wherethe fluoroalkyl group was a perfluoropropyl group. The reactionsdepicted in FIG. 4 were performed using 1.5 equiv of reagent 2 at 50° C.unless otherwise noted. Similar to the trifluoromethylation reactions ofFIGS. 1-3, perfluoropropylarenes 5 were surprisingly and unexpectedlyobtained in good yield under mild reaction conditions, for aromaticiodides 3, including electron-rich and electron-poor aromatic iodidesand aromatic iodides with potentially reactive quinoline and nitroarenefunctionality. The letter designations for the aromatic iodides 3correlate with the letter designations of the correspondingperfluoropropylarenes 5.

Referring to FIG. 4, the yield of nitro-substituted 5j (88%) from thereaction of reagent 2 was higher than that reported fromCuI+KF+TMSCF₂CF₂CF₃ (41%; Urata, H.; Fuchikami, T. Tetrahedron Lett.1991, 32, 91.). The yield of perfluoropropylarene 5q was 99% whenreagent 2 was added as a 1-component reagent. In comparison, the yieldof 5q was 81% when the copper, perfluoropropyl source and ligand wereadded as separate ingredients and the mixture was maintained at 80° C.for 18 h. The same reaction conducted without a glove box gave theproduct 5q in 79% yield (reaction identified with the superscript b).For the reaction identified with the superscript c, the reaction wasperformed at room temperature.

FIG. 5 depicts chemical structures, a reaction scheme and a productyield for a mechanistic study of a fluoroalkylation reaction. Withoutbeing limited by any theory of operation, this study indicated that thetrifluoromethylation of 2-(allyloxy)iodobenzene 3ab does not involve theformation of an aryl radical intermediate. If the trifluoromethylationof 2-(allyloxy)iodobenzene 3ab occurred through an aryl radical, onewould expect to observe cyclized product 6. This product was notdetected by GC-MS, however, and the reaction instead produced thetrifluoromethylarene 4ab in a 91% yield.

FIG. 6 depicts chemical structures, reaction schemes and product yieldsfor examples of fluoroalkylation reactions of aromatic bromides. Similarto the trifluoromethylation reactions of FIGS. 1-3,trifluoromethylarenes 8 were surprisingly and unexpectedly obtained ingood yield for electron-rich, electron-poor and neutral aromaticbromides 7, including aromatic bromides with potentially reactivenitroarene functionality (7j). While the reaction temperature (110° C.)was higher than for the corresponding reactions with aromatic iodides,the reaction conditions for the aromatic bromides were still relativelymild. The letter designations for the aromatic bromides 7 correlate withthe letter designations of the corresponding trifluoromethylarenes 8.

A method of forming a fluorinated molecular entity may include reactingin a reaction mixture a vinyl halide, copper, a fluoroalkyl group and aligand, and forming a fluoroalkylvinyl compound in the reaction mixture.The vinyl halide includes an organic group that contains a vinyl group,and a halogen substituent bonded to a carbon of the vinyl group. Theligand includes at least one group-V donor. The overall molar ratio ofcopper to vinyl halide in the reaction mixture is from 0.5 to 3. Thefluoroalkylvinyl compound formed in the reaction mixture includes theorganic group that contains a vinyl group, and the fluoroalkyl groupbonded to a carbon of the vinyl group.

The copper, fluoroalkyl group, ligand and reaction conditions may be asdescribed above for fluoroalkylation of aromatic halides. An example ofa fluoroalkylation reaction performed with a vinyl halide is provided inExample 12, below.

A composition, which may be useful as a reagent for the abovefluoroalkylation method, consists essentially of copper, a fluoroalkylgroup, and a ligand having at least one group-V donor. The molar ratioof copper to the fluoroalkyl group is approximately 1. Preferably thecomposition is substantially free of solvent.

The fluoroalkyl group preferably has the formula —C_(x)H_((2x-y))F_(y),where x is from 1 to 12 and y is from 1 to (2x+1). Preferred fluoroalkylgroups include —CF₃, —CF₂CF₃, —CH₂CF₃, —CH₂CH₂F, —CF₂CF₂CF₃, —CH₂CF₂CF₃,—CH₂CH₂CF₃, —CH₂CH₂CH₂F, —CH(CF₃)₂ and —CF(CF₃)₂.

The ligand may include at least one group-V donor. Preferably the ligandincludes at least one group-V atom such as phosphorus or nitrogen. Morepreferably the ligand includes at least one group-V atom selected fromthe group consisting of phosphorus, a ring nitrogen of a heterocyclicgroup, and an amine. Examples of ligands that include at least onephosphorus atom, a ring nitrogen of a heterocyclic group or an amineinclude a phenanthroline, an N,N′-disubstituted diamine, a bipyridyl, apyridyl, a phosphine, and a phosphite. Each of these ligands may includeone or more substituent groups. For ligands that include a ringstructure, one or more ring carbons may be replaced with a heteroatom.Specific examples of ligands that include at least one phosphorus atom,a ring nitrogen of a heterocyclic group, or an amine include1,10-phenanthroline (phen), tetramethylenediamine (TMEDA),N,N′-dimethylethylenediamine (DMEDA), N,N′-dimethylcyclohexanediamine(DMECA), bipyridyl (bipy), pyridyl (Py), tributyl phosphine [(n-Bu)₃P],triphenyl phosphine (Ph₃P), trimethyl phosphite [(MeO)₃P], triphenylphosphite [(PhO)₃P] and substituted derivatives of these. A ligandhaving two or more group-V donor atoms may be present in a molar ratiowith the copper of approximately 1. A ligand having only one group-Vdonor atom may be present in a molar ratio with the copper ofapproximately 1 to 2.

In one example, a composition consisting essentially of copper, thefluoroalkyl group, and the ligand may be prepared by combining a coppersource and the ligand in a solvent to form a first mixture, and thenadding a fluoroalkyl group source to form a second mixture. Thecomposition consisting essentially of copper, the fluoroalkyl group, andthe ligand may precipitate out of the solvent, and the precipitate maybe isolated from the mixture, and optionally washed and/or dried, toprovide a composition substantially free of solvent.

Referring to Scheme 1 above, a composition having the molecular formulaof reagent 1 was isolated as an orange-red solid in 96% yield on amultigram scale from the reaction of [CuOtBu]4 and 1,10-phenanthroline,followed by trimethyl(trifluoromethyl)-silane (TMS-CF₃, Ruppert'sreagent) in one pot. Complex 1 was soluble in polar, aprotic solventssuch as DMF and DMSO, partially soluble in THF and CH₂Cl₂, and insolublein less polar solvents such as benzene and Et₂O. The isolated complex 1was stable at room temperature under nitrogen atmosphere for over 1month without decomposition.

Referring to Scheme 1 above, a composition having the molecular formulaof reagent 2 was synthesized in 97% yield by an analogous reactionstarting with commercially available (perfluoropropyl)-trimethylsilaneinstead of Ruppert's reagent.

In another example, a composition consisting essentially of copper, thefluoroalkyl group, and the ligand may be prepared by combining a coppersource that includes a copper-carbon bond or a copper-nitrogen bond, analcohol, a compound including at least one group-V donor, and atri-organo(fluoroalkylsilane). These ingredients may be combined in anyorder, and may be combined in a single step or in two or more steps.Preferably the copper source, the alcohol and the compound including atleast one group-V donor are combined in a first mixture having asolvent, and the tri-organo(fluoroalkylsilane) is added to the firstmixture to form a second mixture. A copper-containing reagent having thegeneral structure [(L)Cu—R_(f)] may precipitate out of the reactionmixture, and the precipitate may be isolated from the mixture, andoptionally washed and/or dried, to provide a composition substantiallyfree of solvent.

Examples of copper sources containing a copper-carbon bond includecopper mesityl, Cu—C₆H₅, Cu-o-tolyl, Cu-2,6-xylyl, a Cu-enolate, acopper acetylide and a copper vinyl compound. Examples of copper sourcescontaining a copper-nitrogen bond include Cu—N(SiCH₃)₂, Cu—N(C₆H₅)₂ andCu—N(CH₃)₂. Examples of alcohols include methanol, ethanol, isopropanol,n-butyl alcohol and t-butyl alcohol. Examples of ligands and oftri-organo(fluoroalkylsilanes) are listed above.

For a compound having two or more group-V donor atoms, the compound maybe present in the first mixture in a molar ratio with the copper of 0.75to 1.5, and preferably is present in the first mixture in a molar ratiowith the copper of approximately 1. For a compound having only onegroup-V donor atom, the compound may be present in a molar ratio withthe copper of 0.75 to 2.5, and preferably is present in the firstmixture in a molar ratio with the copper of approximately 1 to 2. Thetri-organo(fluoroalkylsilane) may be present in the first mixture in amolar ratio with the copper of 0.75 to 1.5, and preferably is present inthe first mixture in a molar ratio with the copper of approximately 1.

Referring to Scheme 2 above, a composition having the molecular formulaof reagent 1 was isolated as an orange-red solid on a multigram scalefrom the reaction of copper mesityl, t-butyl alcohol and1,10-phenanthroline, followed by TMS-CF₃ in one pot. A compositionhaving the molecular formula of reagent 2 was prepared by an analogousreaction starting with commercially availabletrimethyl(perfluoropropylsilane) instead of TMS-CF₃. A compositionhaving the molecular formula of reagent 3 was prepared by an analogousreaction starting with commercially availabletrimethyl(perfluoroethylsilane) instead of TMS-CF₃.

One advantage of this method of preparing a copper-containing reagentusing a copper source containing a copper-carbon bond or acopper-nitrogen bond, relative to the method of Scheme 1, is that thereagent can be prepared on a scale of 20 or more grams per reaction.Another advantage of using this method of preparing a copper-containingreagent is that copper mesityl is simpler to prepare, isolate and storethan is [CuOtBu].

Another composition, which may be useful as a reagent for thefluoroalkylation method, consists essentially of copper, a fluoroalkylgroup, a first ligand having at least one group-V donor, and a secondligand different from the first ligand. The molar ratio of copper to thefluoroalkyl group is approximately 1. Preferably the composition issubstantially free of solvent. The fluoroalkyl group and the firstligand may be as described above.

The second ligand may stabilize the composition from thermal and/oroxidative degradation, and may be released from the copper when thecomposition is added to a reaction mixture. The second ligand mayinclude at least one group-V or group-VI atom, which may be a donoratom. Preferably the ligand includes at least one group-V donor atomsuch as phosphorus or nitrogen and/or at least one group-VI donor atomsuch as oxygen. More preferably the ligand includes phosphorus, a ringnitrogen of a heterocyclic group, an amine, oxygen or sulfur.

Examples of ligands that include at least one phosphorus atom, a ringnitrogen of a heterocyclic group, an amine, an oxygen atom or a sulfuratom include a phenanthroline, an N,N′-disubstituted diamine, abipyridine, a pyridine, a trialkylamine, an azole, a phosphine, aphosphite, an ether, an amide and a sulfide. Each of these ligands mayinclude one or more substituent groups. For ligands that include a ringstructure, one or more ring carbons may be replaced with a heteroatom.Specific examples of ligands that include at least one phosphorus atom,a ring nitrogen of a heterocyclic group, an amine, an oxygen atom or asulfur atom include 1,10-phenanthroline, TMEDA, DMEDA, DMECA, bipy, Py,N-methylimidazole, oxazole, N-methylpyrazole, triethylamine, (n-Bu)₃P,Ph₃P, (MeO)₃P, (PhO)₃P, diethyl ether, THF, DMF, urea, dimethyl sulfide,thiourea, acetate (OAc), and pivalate.

The fluoroalkylation methods and reagents can provide fluoroalkyl areneswith an unprecedented range of aryl iodides at temperatures from roomtemperature to 50° C. In comparison to conventional methods forfluoroalkylation of aromatic halides, this system can react under muchmilder conditions, can tolerate a wider range of functional groups, cantolerate basic heterocycles, reacts with more hindered substrates, andcan be extended to perfluoroalkylation. The method also may be carriedout with a total cost that is much less than the conventionalpalladium-catalyzed systems involving CF₃ nucleophiles or electrophiles.The reagent may be prepared from easily available, inexpensive reagentsin one pot and can be used in situ or as an isolated composition.

The following examples are provided to illustrate one or more preferredembodiments of the invention. Numerous variations can be made to thefollowing examples that lie within the scope of the invention.

EXAMPLES

General Procedures.

All manipulations were conducted under an inert atmosphere using anitrogen-filled glovebox (Innovative Technologies, Newburyport, Mass.)equipped with an oxygen sensor (working oxygen level <20.0 ppm) andlow-temperature refrigeration unit (−30° C.), unless otherwise noted.All reactions were conducted in oven-dried 4-mL or 20-mL vials fittedwith a Teflon-lined screw cap under an atmosphere of nitrogen, unlessotherwise noted.

All reactions were run with anhydrous solvents. The solvents Et₂O, THF,benzene, and toluene were degassed with argon and passed through acolumn of activated alumina in a solvent purification system fromInnovative Technologies. Anhydrous DMF was purchased from Aldrich (St.Louis, Mo.) and used as received.

Materials.

Copper(I) chloride (99.999%) was purchased from STREM CHEMICALS, INC.(Newburyport, Mass.). Copper(I) chloride (≧99%), lithium tert-butoxide(97%), potassium tert-butoxide (95% or ≧97%), anhydrous t-butyl alcohol,1,10-phenanthroline (phen), 2,2′-bipyridyl (bipy),4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy),(perfluoropropyl)trimethylsilane (TMSCF₂CF₂CF₃) and4-(trifluoromethoxy)anisole (internal standard of ¹⁹F NMR analysis) werepurchased from Aldrich. Trimethyl(trifluoromethyl)silane (Ruppert'sreagent, TMSCF₃) was purchased from Matrix Scientific. Iodobenzene (3a),4-iodoanisole (3c), 4-bromoiodobenzene (3e), 4-iodobenzyl alcohol (3f),4-iodoacetophenone (3g), 4-iodobenzaldehyde (3h), 4-iodobenzonitrile(3i), 4-nitroiodobenzene (3j), 2-iodotoluene (3k), 2-iodoanisole (3l),2-iodo-1,3-dimethylbenzene (3n), 1-iodo-2,6-dimethoxybenzene (3o),4-iodobiphenyl (3q), 4-(benzyloxy)iodobenzene (3r), ethyl 4-iodobenzoate(3t), 7-chloro-4-iodoquinoline (3×) were purchased from Aldrich.4-Butyliodobenzene (3b) and 3-iodopyridine (3p) were purchased from AlfaAesar. 2-Chloroiodobenzene (3m) was purchased from Lancaster. All thecommercially available reagents were used as received. [CuOtBu]4 wasprepared from CuCl (Strem) and LiOtBu according to literature procedures(Tsuda, T.; Hashimoto, T.; Saegusa, T. J. Am. Chem. Soc. 1972, 94, 658.;Lemmen, T. H.; Goeden, G. V.; Huffman, J. C.; Geerts, R. L.; Caulton, K.G. Inorg. Chem. 1990, 29, 3680.)

The following were prepared according to the literature procedures:4-Iodo-N,N-dimethylaniline (3d; Monnereau, C.; Blart, E.; Odobel, F.Tetrahedron Lett. 2005, 46, 5421.), N-(4-iodophenyl)acetamide (3s;Bjornestedt, R.; Zhong, G.; Lerner, R. A.; Barbas III, C. F. J. Am.Chem. Soc. 1996, 118, 11720.), 4-formyl-2-iodo-6-methoxyphenyl acetate(3u; Liao, Y.; Fathi, R.; Yang, Z. WO2004000764.),1,3-bis(benzyloxymethyl)-5-iodopyrimidine-2,4(1H,3H)-dione (3w; DeFrees,S. A.; Reddy, K. S.; Cassady, J. M. Synth. Commun. 1988, 18, 213.),N-tert-butoxycarbonyl-5-iodoindole (3y; Furuya, T.; Storm, A. E.;Ritter, T. J. Am. Chem. Soc. 2009, 131, 1662.), ethyl3-chloro-2-iodobenzoate (3z; Lin, W.; Baron, O.; Knochel, P. Org. Lett.2006, 8, 5673.),(R)-3,3′-diiodo-2,2′-bis(methoxymethoxy)-1,1′-binaphthyl (3aa; Wu, T.R.; Shen, L.; Chong, J. M. Org. Lett. 2004, 6, 2701.; Milburn, R. R.;Hussain, S. M. S.; Prien, O.; Ahmed, Z.; Snieckus, V. Org. Lett. 2007,9, 4403.), and 1-(allyloxy)-2-iodobenzene (3ab; Molander, G. A.;Harring, L. S. J. Org. Chem. 1990, 55, 6171.).

1-Bromo-4-[(4-iodobenzyloxy)methyl]benzene (3v) was prepared using annon-optimized procedure as follows. To a stirred solution of4-iodobenzyl alcohol (1.33 g, 5.5 mmol, 1.1 equiv) in DMF (40 mL) at 0°C. was added NaH (240 mg, 60% in mineral oil, 6.0 mmol, 1.2 equiv), andthe mixture was warmed to room temperature and stirred for 30 min. Themixture was cooled to 0° C., and 4-bromobenzyl bromide (1.25 g, 5.0mmol, 1.0 equiv) and tetra-n-butylammonium iodide (92.3 mg, 0.25 mmol,0.050 equiv) were added. The reaction mixture was warmed to roomtemperature, stirred for 2 h and quenched with saturated aqueous NH₄Clsolution. The mixture was extracted with Et₂O, and the organic layer waswashed with 1 M aqueous HCl solution and brine and dried over Na₂SO₄.After evaporation of the solvent, the crude mixture was purified byflash silica gel column chromatography (hexane/Et₂O=400/1 to 20/1) togive 1-bromo-4-[(4-iodobenzyloxy)methyl]benzene (3v) as a white solid(1.02 g, 51% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.68 (d, J=8.4 Hz, 2H),7.48 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H),4.49 (s, 4H). ¹³C{¹H} NMR (125 MHz, CDCl₃): δ 137.9, 137.8, 137.2,131.8, 129.8, 129.6, 121.9, 93.4, 71.8, 71.7. Anal. calcd. forC₁₄H₁₂BrIO: C, 41.72; H, 3.00. Found: C, 41.71; H, 2.77.

Instrumentation.

Organic solutions were concentrated by rotary evaporation at 25-40° C.Flash silica gel column chromatography was conducted with SilicycleSilica-P Flash Silica Gel, eluting with pentane or a mixture of pentaneand Et₂O. TLC was conducted with EMD Silica Gel 60 F₂₅₄ (250 micrometerlayer thickness). The products were visualized by UV light and stainingwith ceric ammonium molybdate (CAM).

NMR spectra were acquired on 400 MHz and 500 MHz Varian Unity or Innovainstruments at the University of Illinois VOICE NMR facility. NMRspectra were processed with MestReNova 5.0 (Mestrelab Research SL).Chemical shifts are reported in ppm and referenced to residual solventpeaks (CHCl₃ in CDCl₃: 7.26 ppm for ¹H and 77.0 ppm for ¹³C; DMF-d₆ inDMF-dr: 2.91 ppm for ¹H and 162.7 ppm for ¹³C) or to an externalstandard (1% CFCl₃ in CDCl₃: 0 ppm for ¹⁹F). Coupling constants arereported in hertz. Benzene-d₆ and DMF-d₇ were dried over activated MS 4Aprior to use. THF-d₈ and dichloromethane-d₂ were purchased from Aldrichand used as received.

All GC-MS analyses were conducted with an Agilent 6890N GC equipped withan HP-5 column (25 m×0.20 mm ID×0.33 micrometer film) and an Agilent5973 Mass Selective Detector. The temperature for each run was held at50° C. for 2 min, ramped from 50° C. to 300° C. at 5° C./min, and heldat 300° C. for 5 min.

Elemental analyses were performed by the University of Illinois atUrbana-Champaign Microanalysis Laboratory and by Robertson MicrolitLaboratories, Inc. (Madison, N.J.). Optical rotations were measured on aRudolph Instruments (Denville, N.J.) Autopol IV polarimeter.

Example 1 Formation of (1,10-Phenanthroline)(trifluoromethyl)copper(I)(1)

To an oven-dried 250-mL round-bottomed flask equipped with a stir barwere added [CuOtBu]4 (1.094 g, 2.00 mmol, 8.00 mmol for monomericCuOtBu), 1,10-phenanthroline (1.442 g, 8.00 mmol, 1.00 equiv) andbenzene (80 mL). The flask was sealed with a septum and the dark purplemixture was stirred at room temperature for 30 min, then TMSCF₃ (1.31mL, 8.80 mmol, 1.1 equiv) was added dropwise. The mixture was stirred atroom temperature for 18 h to give a red-orange suspension. Thesuspension was filtered through a medium fritted funnel, and the solidwas washed with Et₂O (50 mL) and dried under vacuum to give(1,10-phenanthroline)-(trifluoromethyl)copper(1) (1) as an orange solid(2.397 g, 96% yield).

¹H NMR (400 MHz, DMF-d₇) δ 9.18 (d, J=4.2 Hz, 2H), 8.89 (d, J=8.0 Hz,2H), 8.31 (s, 2H), 8.10 (dd, J=4.2, 8.0 Hz, 2H). ¹³C{¹H} NMR (100 MHz,DMF-d₇) δ 150.4, 144.2, 138.3, 130.0, 127.8, 126.5 (note that a carbonpeak for CF₃ was not observed due to (1) dynamic behavior of the complex(see below), (2) broadening the peak through Cu—C coupling and (3)splitting of the peak through C—F coupling). ¹⁹F NMR (376 MHz, DMF-d₇):−22.6 (br), −30.9 (s). Anal. Calcd for C₁₃H₈CuN2F3: C, 49.92; H, 2.58;N, 8.96; F, 18.22. Found: C, 49.74; H, 2.52; N, 8.99; F, 18.17.

Example 2 Characterization of (phen)Cu—CF₃ (1)

Conductivity Measurements:

To a 5-mL volumetric flask was added(1,10-phenanthroline)(trifluoromethyl)copper(I) (1) (15.6 mg, 0.050mmol), and DMF was added to the flask to the 5 mL mark to give a 0.010 Msolution of 1 in DMF. A portion of the 0.010 M solution (0.50 mL, 0.0050mmol) was transferred to another 5-mL volumetric flask and diluted withDMF to the 5 mL mark to give a 1.0 mM solution of 1. The conductivity ofthe 1.0 mM solution of 1 was 26 Ω⁻¹ cm²mol⁻¹. The same procedure wasfollowed for the reference samples ferrocene (neutral) andtetra-n-butylammonium tetraphenylborate (ionic), and the conductivityfor these samples was 0.5 and 50.5 Ω⁻¹ cm²mol⁻¹, respectively.

¹⁹F NMR Peak Ratio in Different Solvents:

(1,10-Phenanthroline) (trifluoromethyl)copper(I) (1) (2.2 mg, 0.0070mmol) was dissolved in either dichloromethane-d₂, THF-d₈ or DMF-d₇ (0.70mL, 0.010 M for 1), and the ratio of the two peaks at −22.6 and −30.9ppm was measured by ¹⁹F NMR analysis. The observed ratio was 76/24 indichloromethane-d₂, 68/32 in THF-d₈, and 21/79 in DMF-d₇.

Dynamic Behavior in Solution:

The ¹⁹F NMR spectrum of 1 in DMF-d₇ consisted of two peaks at −22.6 and−30.9 ppm. Based on the peak ratio observed in the solvents withdifferent polarity, we proposed that the peak at −30.9 ppm correspondedto species with the ionic “double salt” structure([(phen)₂Cu][Cu(CF₃)₂]) and the peak at −22.6 ppm to a species with theneutral structure (phen)CuCF₃. The presence of ionic species in solutionwas verified by the conductivity measurement of 1 in DMF describedabove. This structural assignment agrees with the previous reports byBurton (Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832.)and Vicic (Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organometallics2008, 27, 6233.) in which two ¹⁹F NMR resonances were reported for theN-heterocyclic carbene-ligated copper trifluoromethyl complex. Thedynamic behavior of 1 in solution was also evidenced by the differentpeak ratio in the solvents with different polarity.

Example 3 Formation of (1,10-Phenanthroline)(perfluoropropyl)copper(I)(2)

To a 40-mL vial equipped with a stir bar were added [CuOtBu]4 (274 mg,0.50 mmol, 2.00 mmol for monomeric CuOtBu, 1.0 equiv),1,10-phenanthroline (360 mg, 2.00 mmol, 1.00 equiv) and benzene (20 mL).The dark purple mixture was stirred at room temperature for 30 min, atwhich time TMSCF₂CF₂CF₃ (446 μL, 1.1 mmol, 1.1 equiv) was addeddropwise. The mixture was stirred at room temperature for 18 h to give adark purple suspension. The suspension was filtered through a mediumfritted funnel, and the solid was washed with Et₂O (10 mL) and driedunder vacuum to give (1,10-phenanthroline)(perfluoropropyl)copper(I) (2)as a brown solid (801 mg, 97% yield). The same reaction was alsoperformed on 3.0 mmol scale using 411 mg of [CuOtBu]₄, 669 mg of1,10-phenanthroline and 669 μL of TMSCF₂CF₂CF₃ in 30 mL of benzene togive 2 (1149 mg, 93% yield).

¹H NMR (400 MHz, DMF-d₇) δ 9.16 (s, 2H), 8.87 (brs, 2H), 8.26 (brs, 2H),8.12-8.09 (m, 2H). ¹³C NMR (125 MHz, DMF-d₇) δ 162.9, 162.7, 162.5,150.6, 144.3, 144.3, 138.4, 130.0, 127.8, 126.5 (note that a carbon peakfor CF₃ was not observed due to (1) dynamic behavior of the complex (seebelow), (2) broadening the peak through Cu—C coupling and (3) splittingof the peak through C—F coupling). ¹⁹F NMR (375 MHz, DMF-d₇) δ −79.6,−80.3 (t, J_(C—F)=8.9 Hz) −109.6, −117.4, −125.2, −127.2. Anal. Calcdfor C₁₅H₈CuN2F7: C, 43.65; H, 1.95; N, 6.79. Found: C, 43.56; H, 2.03;N, 6.95. Conductivity (1 mM in DMF): 13.2 Ω⁻¹ cm²mol⁻¹.

Example 4 Fluoroalkylation Reactions of Aromatic Iodides (3) Using(phen)Cu—CF₃ (1) as Limiting Agent

To a 4-mL vial equipped with a stir bar were added 1 (10.9 mg, 0.035mmol), ArI 3 (if solid, 0.175 mmol, 5.0 equiv) and4-(trifluoromethoxy)anisole (internal standard for ¹⁹F NMR analysis) inDMF (0.70 mL, 0.050 M, 0.035 mmol). To the mixture was added ArI 3 (ifliquid, 0.175 mmol, 5.0 equiv), and the mixture was stirred at roomtemperature. After 18 h, the stirring was stopped, and the reactionmixture was transferred to an NMR tube, and the yield of the product wasmeasured by ¹⁹F NMR analysis with the following parameters afterreduction of the sw (sweep width) to include both standard (−58.6 ppm)and product peaks: at =10 (s), d1=10 (s), pw90=15.5 (μs), pw=15.5 (μs)and nt=4. Structures and yields for products 4a-4p are shown in FIG. 1.

Example 5 Comparison of (phen)Cu—CF₃ (1) and [(SiMes)₂Cu][Cu(CF₃)₂]

[(SIMes)₂Cu][Cu(CF₃)₂] was prepared according to literature procedures(Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organometallics 2008, 27,6233.). To a 4-mL vial equipped with a stir bar were charged 1 (7.8 mg,0.025 mmol) or [(SIMes)₂Cu][Cu(CF₃)₂] (11.0 mg, 0.025 mmol) and4-(trifluoromethoxy)anisole in either DMF or a mixture of DMI andbenzene (1.5/7.5) (0.050 M, 0.50 mL, 0.025 mmol). To the mixture wasadded ArI 3b (22 μL, 0.13 mmol, 5.0 equiv), and the mixture was stirredat room temperature (for DMF; standard conditions for 1) or 50° C. (forDMI/benzene; standard conditions reported by Dubinina et al.). After 1and 18 h (for DMF) or 1, 12 and 28 h (for DMI/benzene), the mixture wastransferred to an NMR tube, and the yield of the product 4b was measuredby ¹⁹F NMR analysis. The yields of the product 4b were: 19 (1 h) and 88(18 h) % for the reaction of 1 in DMF; 0.7 (1 h) and 8.7 (18 h) % forthe reaction of [(SIMes)₂Cu][Cu(CF₃)₂] in DMF; 85 (1 h), 92 (12 h) and91 (28 h) % for the reaction of 1 in DMI/benzene; 8.3 (1 h), 53 (12 h)and 70 (28 h) % for the reaction of [(SIMes)₂Cu][Cu(CF₃)₂] inDMI/benzene.

Example 6 Fluoroalkylation Reactions With (phen)Cu—CF₃ (1) and UsingAromatic Iodide (3) as Limiting Agent

To a 20-mL vial equipped with a stir bar was added ArI 3 (if solid, 0.50mmol), 1 (235 mg, 0.75 mmol, 1.5 equiv) and DMF (2.0 mL). Then ArI 3 (ifliquid, 0.50 mmol) was added, and the mixture was stirred at roomtemperature or 50° C. After 18 h, the stirring was stopped, and thereaction mixture was diluted with Et₂O and filtered through a pad ofCelite. The Celite pad was washed with Et₂O. The combined filtrate waswashed with 1M aqueous HCl, saturated aqueous NaHCO₃ solution and brine,and dried over Na₂SO₄. After filtration and evaporation of the solvent,the crude mixture was purified by flash silica gel column chromatographyusing pentane/Et₂O or pentane as eluent to give ArCF₃ 4. Structures andyields for the products are shown in FIG. 2, and experimental detailsare below.

4-(Trifluoromethyl)anisole (4c; Iwanaga, K.; Kobayashi, J.; Kawashima,T. Tetrahedron 2007, 63, 10127.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4c (51.6 mg, 59% yield). The isolated yield of 4c waslow due to volatility of the product. The same reaction was performedunder the same reaction condition with 4-CF₃₀C₆H₄OMe (0.50 mmol, 1.0equiv) as internal standard to give 4c (92%, NMR yield). Pentane wasused as eluent for column chromatography. ¹H NMR (500 MHz, CDCl₃) δ:7.56 (d, 2H, J=9.0 Hz), 6.67 (d, 2H, J=9.0 Hz), 3.85 (s, 3H). ¹³C{¹H}NMR (125 MHz, CDCl₃) δ: 162.0, 126.9 (q, J_(C—F)=3.9 Hz), 124.5 (q,J_(C—F)=270 Hz), 122.6 (q, J_(C—F)=32.5 Hz), 113.9, 55.4. ¹⁹F NMR (469MHz, CDCl₃) δ: −62.0.

4′-(Trifluoromethyl)acetophenone (4g; Arisawa, M.; Suwa, K.; Yamaguchi,M. Org. Lett. 2009, 11, 625.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4g (55.7 mg, 54% yield). The isolated yield of 4g waslow due to volatility of the product. The same reaction was performedunder the same reaction condition with 4-CF₃₀C₆H₄OMe (0.50 mmol, 1.0equiv) as internal standard to give 4g (93% NMR yield). Pentane was usedas eluent for column chromatography. ¹H NMR (500 MHz, CDCl₃) δ: 8.05 (d,2H, J=8.0 Hz), 7.72 (d, 2H, J=8.0 Hz), 2.64, (s, 3H). ¹³C{¹H} NMR (125MHz, CDCl₃) δ: 196.9, 139.6, 134.4 (q, J_(C—F)=32.5 Hz), 128.6, 125.6(q, J_(C—F)=3.6 Hz), 123.6 (q, J_(C—F)=271 Hz), 26.7. ¹⁹F NMR (469 MHz,CDCl₃) δ: −63.6.

4-(Trifluoromethyl)biphenyl (4q; Ackermann, L.; Potukuchi, H. K.;Althammer, A.; Born, Robert.; Mayer, Peter. Org. Lett. 2010, 12, 1004.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4q (92.2 mg, 83% yield). The same reaction wasperformed using 1.2 equiv of 1 at rt for 18 h to give 4q (102.3 mg, 92%yield). Pentane was used as eluent for column chromatography. ¹H NMR(400 MHz, CDCl₃) δ: 7.76-7.66 (m, 4H), 7.64-7.58 (m, 2H), 7.52-7.41 (m,3H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 144.7, 139.7, 130.1 (q,J_(C—F)=32.2 Hz), 129.0, 128.2, 127.4, 127.3, 125.7 (q, J_(C—F)=3.8 Hz),124.3 (q, J_(C—F)=271 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ: −62.8. Anal.Calcd for C₁₃H₉F₃: C, 70.27; H, 4.08. Found: C, 69.98; H, 3.98.

The reaction was also conducted outside glove box. In this case, 1 (0.75mmol, 1.5 equiv) and 3q (0.50 mmol) were weighted into a 20-mL vialoutside glove box and the vial was evacuated and refilled with drynitrogen (twice). Then DMF (2.0 mL) was added and the reaction mixturewas stirred at 50° C. for 18 h to give 4q (101.8 mg 92% yield).

1-(Benzyloxy)-4-(trifluoromethyl)benzene (4r; Pratt, D. A.; de Heer, M.I.; Mulder, P.; Ingold, K. U. J. Am. Chem. Soc. 2001, 123, 5518.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4r (118.1 mg, 89% yield). Pentane was used as eluentfor column chromatography. ¹H NMR (400 MHz, CDCl₃) δ: 7.46-7.37 (m, 7H),7.07 (d, 2H, J=8.8 Hz), 5.17, (s, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ:161.1, 136.2, 128.7, 128.2, 127.4, 126.9 (q, J_(C—F)=3.6 Hz), 124.4 (q,J_(C—F)=270 Hz), 123.0 (q, J_(C—F)=32.6 Hz), 114.8, 70.1. ¹⁹F NMR (469MHz, CDCl₃) δ: −61.9. Anal. Calcd for C₁₄H₁₁F₃₀: C, 66.66; H, 4.40.Found: C, 66.41; H, 4.21.

N-[4-(Trifluoromethyl)phenyl]acetamide (4s; O'Connor, C. J.; McLennan,D. J.; Calvert, D. J.; Lomax, T. D.; Porter, A. J.; Rogers, D. A. Aust.J. Chem. 1984, 37, 497.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4s (86.8 mg, 83% yield). The same reaction wasperformed using 1.5 equiv of 1 at rt for 18 h to give 4s (101.8 mg,quantitative). Pentane/ether mixture (2/1 to 0/1) was used for columnchromatography. ¹H NMR (500 MHz, CDCl₃) δ: 7.64-7.55 (m, 5H), 2.21 (s,3H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 168.8, 140.9, 126.2 (q, J_(C—F)=3.6Hz), 125.8 (q, J_(C—F)=31.4 Hz), 124.0 (q, J_(C—F)=270 Hz), 119.4, 24.6.¹⁹F NMR (469 MHz, CDCl₃) δ: −62.3.

Ethyl 4-(trifluoromethyl)benzoate (4t; Shang, R.; Fu, Y.; Li, J.-B.;Zhang, S.-L.; Guo, Q.-X.; Liu, L., J. Am. Chem. Soc. 2009, 131, 5738.;Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4t (34.5 mg, 32% yield). The isolated yield of 4t waslow due to volatility of the product. The same reaction was performedunder the same reaction condition with 4-CF₃₀C₆H₄OMe as internalstandard (0.50 mmol, 1.0 equiv) to give 4t (94%, NMR yield). Pentane wasused as eluent for column chromatography. ¹H NMR (500 MHz, CDCl₃) δ:8.15 (d, 2H, J=8.0 Hz), 7.70 (d, 2H, J=8.0 Hz), 4.41 (q, 2H, J=7.0 Hz),1.41, (t, 3H, J=7.0 Hz). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 165.4, 134.3(q, J_(C—F)=32.6 Hz), 133.7, 129.9, 125.3 (q, J_(C—F)=3.8 Hz), 123.6 (q,J_(C—F)=271 Hz), 61.5, 14.2. ¹⁹F NMR (469 MHz, CDCl₃) δ: −63.6.

4-Formyl-2-methoxy-6-(trifluoromethyl)phenyl acetate (4u):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4u (89.0 mg, 68% yield). Pentane/Ether=5/1 was used forcolumn chromatography. ¹H NMR (500 MHz, CDCl₃) δ: 9.97 (s, 1H), 7.74 (s,1H), 7.67 (s, 1H), 3.94 (s, 3H), 2.36 (s, 3H). ¹³C{¹H} NMR (125 MHz,CDCl₃) δ: 189.7, 167.2, 153.1, 142.9 (q, J_(C—F)=1.6 Hz), 134.5, 125.2(q, J_(C—F)=32.1 Hz), 122.2 (q, J_(C—F)=272 Hz), 121.2 (q, J_(C—F)=4.6Hz), 113.9, 56.6, 20.2. ¹⁹F NMR (469 MHz, CDCl₃) δ: −62.7. Anal. Calcdfor C₁₁H₉F₃O₄: C, 50.39; H, 3.46. Found: C, 50.43; H, 3.29.

1-(4-Bromobenzyloxymethyl)-4-(trifluoromethyl)benzene (4v):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4v (154.4 mg, 89% yield). The same reaction wasperformed using 1.5 equiv of 1 at rt for 18 h to give 4v (145.0 mg, 84%yield). Pentane was used for column chromatography. ¹H NMR (400 MHz,CDCl₃) δ: 7.63 (d, 2H, J=8.0 Hz), 7.52-7.47 (m, 4H), 7.27-7.25 (m, 2H),4.61, (s, 2H), 4.54 (s, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 142.1,136.8, 131.6, 129.8 (q, J_(C—F)=32.1 Hz), 129.3, 127.6, 125.3 (q,J_(C—F)=3.8 Hz), 124.1 (q, J_(C—F)=271 Hz), 120.9, 71.7, 71.3. ¹⁹F NMR(469 MHz, CDCl₃) δ: −62.9. Anal. Calcd for C₁₅H₁₂BrF₃O: C, 52.20; H,3.50. Found: C, 52.47; H, 3.78.

1,3-Bis(benzyloxymethyl)-5-(trifluoromethyl)pyrimidine-2,4(1H,3H)-dione(4w; DeFrees, S. A.; Reddy, K. S.; Cassady, J. M. Synth. Commun. 1988,18, 213.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4w (162.9 mg, 78% yield). Ether and EtOAc was used forextraction. Pentane/Ether=2/1 was used for column chromatography. ¹H NMR(500 MHz, CDCl₃) δ: 7.66 (s, 1H), 7.37-7.25 (m, 10H), 5.45 (s, 2H), 5.26(s, 2H), 4.70 (s, 2H), 4.64 (s, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ:158.1, 150.5, 142.4, (q, J_(C—F)=11.5 Hz), 137.6, 136.2, 128.7, 128.5,128.4, 127.9, 127.8, 127.6, 121.5 (q, J_(C—F)=269 Hz), 105.3 (q,J_(C—F)=33.1 Hz), 77.7, 72.6, 72.6, 70.6. ¹⁹F NMR (469 MHz, CDCl₃) δ:−64.5. Anal. Calcd for C₂₁H₁₉F₃N₂O₄: C, 60.00; H, 4.56; N, 6.66. Found:C, 60.17; H, 4.49; N, 6.67.

7-Chloro-4-(trifluoromethyl)quinoline (4x):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4x (102.8 mg, 89% yield). The same reaction wasperformed using 1.2 equiv of 1 at rt for 18 h to give 4x (106.4 mg, 92%yield). In this substrate, different quenching method was used. Afterstirring 18 h, the mixture was poured into 29% aqueous ammoniumhydroxide solution (20 mL) and extracted with ether (20 mL×3). Then, theorganic layers were combined and dried over anhydrous NaSO₄ andfiltrated and evaporated. The resulting crude mixture was diluted withether and wash 1 M HCl, sat. NaHCO₃ and brine, then dried over Na₂SO₄.After filtration and evaporation of the solvent, the crude mixture waspurified by flash silica gel column chromatography usingpentane/Et₂O=10/1 as eluent to give ArCF₃ 4x. ¹H NMR (500 MHz, CDCl₃) δ:9.02 (d, 1H, J=4.0 Hz), 8.18 (d, 1H, J=1.5 Hz), 8.03 (d, 1H, J=8.5 Hz),7.66 (d, 1H, J=4.0 Hz), 7.60 (dd, 1H, J=8.5, 1.5 Hz). ¹³C{¹H} NMR (125MHz, CDCl₃) δ: 150.6, 149.3, 136.3, 134.3 (q, J_(C—F)=32.0 Hz), 129.3,125.2 (q, J_(C—F)=2.1 Hz), 123.1 (q, J_(C—F)=273 Hz), 121.2, 119.8,118.0 (q, J_(C F)=5.3 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ: −62.0. Anal.Calcd for C₁₀H₅ClF3N: C, 51.86; H, 2.18; N, 6.05. Found: C, 51.82; H,1.99; N, 5.91.

tert-Butyl 5-(trifluoromethyl)-1H-indole-1-carboxylate (4y):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4y (141.2 mg, 99% yield). The same reaction wasperformed using 1.5 equiv of 1 at rt for 18 h to give 4y (145.2 mg,quantitative). Pentane/Ether=10/1 was used for column chromatography. ¹HNMR (400 MHz, CDCl₃) δ: 8.26 (d, 1H, J=8.8 Hz), 7.85 (d, 1H, J=1.2 Hz),7.69 (d, 1H, J=3.6 Hz), 7.56 (dd, 1H, J=8.8, 1.2 Hz), 6.63 (d, 1H, J=3.6Hz), 1.69 (s, 9H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 149.3, 136.7, 130.1,127.5, 124.9 (q, J_(C—F)=32.0 Hz), 124.8 (q, J_(C—F)=270 Hz), 120.9 (q,J_(C—F)=3.3 Hz), 118.3 (q, J_(C—F)=4.0 Hz), 115.4, 107.3, 84.4, 28.1.¹⁹F NMR (376 MHz, CDCl₃) δ: −61.5. Anal. Calcd for C₁₄H₁₄F₃NO₂: C,58.95; H, 4.95; N, 4.91. Found: C, 58.63; H, 5.16; N, 4.93.

Ethyl 3-chloro-2-(trifluoromethyl)benzoate (4z):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4z (87.7 mg, 69% yield). Pentane/Ether=5/1 was used forcolumn chromatography. ¹H NMR (400 MHz, CDCl₃) δ: 7.52 (d, 2H, J=8.0Hz), 7.50 (dd, 2H, J=8.0, 8.0 Hz), 7.38 (d, 2H, J=8.0 Hz), 4.38 (q, 2H,J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ:167.4, 135.3 (q, J_(C—F)=2.5 Hz), 133.6 (q, J_(C—F)=1.9 Hz), 133.0,132.4, 126.5, 125.4 (q, J_(C—F)=31.4 Hz), 122.4 (q, J_(C—F)=274 Hz),62.5, 13.8. ¹⁹F NMR (376 MHz, CDCl₃) δ: −58.4. Anal. Calcd forC₁₀H₈ClF₃O₂: C, 47.54; H, 3.19. Found: C, 47.65; H, 3.56.

(R)-2,2′-Bis(methoxymethoxy)-3,3′-bis(trifluoromethyl)-1,1′-binaphthyl(4aa; Kobayashi, S.; Ishitani, H. JP2001139508.; Wu, T. R.; Shen, L.;Chong, J. M. Org. Lett. 2004, 6, 2701.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 1 at 50° C.for 18 h to give 4aa (246.3 mg, 97% yield). Pentane/Ether=5/1 was usedfor column chromatography. ¹H NMR (500 MHz, CDCl₃) δ: 8.39 (s, 2H), 8.02(d, 2H, J=8.0 Hz), 7.55 (dd, 2H, J=7.5, 7.5 Hz), 7.45 (dd, 2H, J=7.5,7.5 Hz), 7.28 (d, 2H, J=9.0 Hz), 4.81 (d, 2H, J=5.5 Hz), 4.57 (d, 2H,J=5.5 Hz), 2.74, (s, 6H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 150.8, 135.6,129.2, 129.1, 129.1, 129.0, 129.0, 128.9 (From 129.2 to 128.9, somepeaks were overlapped and C—F coupling constant of the carbon wasdifficult to analyze), 126.8, 126.2, 126.0, 123.8 (q, J_(C—F)=30.1 Hz),123.6 (q, J_(C—F)=271 Hz), 99.7 (q, J_(C—F)=1.4 Hz), 56.2. ¹⁹F NMR (469MHz, CDCl₃) δ: −61.2. Anal. Calcd for C₂₆H₂₀F₆O₄: C, 61.18; H, 3.95.Found: C, 60.98; H, 3.68.

Example 7 Generation of (phen)Cu—CF₃ in situ And SubsequentFluoroalkylation Reactions Using Aromatic Iodide (3) as Limiting Agent

General Procedure in Glove Box:

To a 20-mL vial equipped with a stir bar were added CuCl (99 mg, 1.0mmol, 2.0 equiv.), KOtBu (112 mg, 1.0 mmol, 2.0 equiv.) and1,10-phenanthroline (180 mg, 1.0 mmol, 2.0 equiv.), and DMF (2.0 mL) wasadded. The dark red mixture was stirred at room temperature for 30 minthen TMSCF₃ (0.148 mL, 1.0 mmol, 2.0 equiv.) was added dropwise. Theresulting mixture was further stirred at room temperature for 1 h andthen ArI 3 (0.50 mmol) was added. The resulting mixture was stirred at50° C. for 18 h, then cooled, diluted with Et₂O and filtered through apad of Celite. The Celite pad was washed with Et₂O and the combinedorganic layer was washed with 1M aqueous HCl, saturated aqueous NaHCO₃solution and brine, and dried over Na₂SO₄. After filtration andevaporation of the solvent, the crude mixture was purified by flashsilica gel column chromatography using pentane/Et₂O as eluent to giveArCF₃ 4.

General Procedure Outside Glove Box:

To a 20-mL vial equipped with a stir bar and a Teflon-lined screw capwas added CuCl (99 mg, 1.0 mmol, 2.0 equiv.) then air in the vial wasevacuated and dry nitrogen was refilled (once) and were added KOtBu (112mg, 1.0 mmol, 2.0 equiv.) and 1,10-phenanthroline (180 mg, 1.0 mmol, 2.0equiv.) then air in the vial was evacuated and dry nitrogen was refilled(twice). To the mixture was added DMF (2.0 mL), and the dark red mixturewas stirred at room temperature for 30 min under nitrogen then TMSCF₃(0.148 mL, 1.0 mmol, 2.0 equiv.) was slowly added. The resulting mixturewas further stirred at room temperature for 1 h and the stirring wasstopped. Then the screw cap was removed and ArI 3 (0.50 mmol) wasexpeditiously added. While opening the cap, surface of the vial turnedgreen, implying partial decomposition of the copper reagent. The cap ofthe vial was closed tightly and the vial was evacuated and refilled withdry nitrogen. The resulting mixture was stirred at 50° C. for 18 h, thencooled, diluted with Et₂O and filtered through a pad of Celite. TheCelite pad was washed with Et₂O and the combined organic layer waswashed with 1M aqueous HCl, saturated aqueous NaHCO₃ solution and brine,and dried over Na₂SO₄. After filtration and evaporation of the solvent,the crude mixture was purified by flash silica gel column chromatographyusing pentane/Et₂O as eluent to give ArCF₃₄.

Structures and yields for the products are shown in FIG. 3, andexperimental details are below.

4-(Trifluoromethyl)biphenyl (4q; Ackermann, L.; Potukuchi, H. K.;Althammer, A.; Born, Robert.; Mayer, Peter. Org. Lett. 2010, 12, 1004.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of CuCl,KOtBu, 1,10-phenanthroline and TMSCF₃ at 50° C. for 18 h at Glove Box togive 4q (105.3 mg, 95% yield). The same reaction was performed atoutside Glove Box using 2.0 equiv of CuCl, KOtBu, 1,10-phenanthrolineand TMSCF₃ at 50° C. for 18 h to give 4q (99.0 mg, 89% yield). The samereaction was performed at outside Glove Box using 1.5 equiv of CuCl,KOtBu, 1,10-phenanthroline and TMSCF₃ at 50° C. for 18 h to give 4q(104.1 mg, 94% yield).

1-(Benzyloxy)-4-(trifluoromethyl)benzene (4r; Pratt, D. A.; de Heer, M.I.; Mulder, P.; Ingold, K. U. J. Am. Chem. Soc. 2001, 123, 5518.):

Reaction was performed outside of a Glove Box using 2.0 equiv of CuCl,KOtBu, 1,10-phenanthroline and TMSCF₃ at 50° C. for 18 h to give 4r(119.5 mg, 95% yield).

4′-(Trifluoromethyl)acetophenone (4g; Arisawa, M.; Suwa, K.; Yamaguchi,M. Org. Lett. 2009, 11, 625.):

Reaction was performed outside of a Glove Box using 2.0 equiv of CuCl,KOtBu, 1,10-phenanthroline and TMSCF₃ at 50° C. for 18 h to give 4g(76.0 mg, 79% yield). The same reaction was performed under the samereaction condition with internal standard (p-CF₃₀C₆H₄OMe; 1.0 eq) togive 4g (85%, NMR yield).

7-Chloro-4-(trifluoromethyl)quinoline (4x):

Reaction was performed outside of a Glove Box using 2.0 equiv of CuCl,KOtBu, 1,10-phenanthroline and TMSCF₃ at 50° C. for 18 h to give 4x(106.4 mg, 92% yield).

tert-Butyl 5-(trifluoromethyl)-1H-indole-1-carboxylate (4y):

Reaction was performed outside of a Glove Box using 2.0 equiv of CuCl,KOtBu, 1,10-phenanthroline and TMSCF₃ at 50° C. for 18 h to give 4y(118.3 mg, 83% yield).

Example 8 Fluoroalkylation Reactions With (phen)Cu—CF₂CF₂CF₃ (2) andUsing Aromatic Iodide (3) as Limiting Agent

To a 20-mL vial equipped with a stir bar was added ArI 3 (0.50 mmol), 2(310 mg, 0.75 mmol, 1.5 equiv) and DMF (2.0 mL). And the mixture wasstirred at 50° C. After 18 h, the stirring was stopped, and the reactionmixture was diluted with Et₂O and filtered through a pad of Celite. TheCelite pad was washed with Et₂O. The combined filtrate was washed with1M aqueous HCl, saturated aqueous NaHCO₃ solution and brine, and driedover Na₂SO₄. After filtration and evaporation of the solvent, the crudemixture was purified by flash silica gel column chromatography usingpentane/Et₂O or pentane as eluent to give ArCF₂CF₂CF₃ 5. Structures andyields for the products 5q, 5r, 5j, 5x and 5y are shown in FIG. 4, andexperimental details are below.

4-(Perfluoropropyl)biphenyl (5q; Fialkov, Yu. A.; Shelyazhenko, S. V.;Yagupol'skii, L. M. Zh. Org. Khim. 1983, 19, 1048.):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 2 at 50° C.for 18 h to give 5q (158.9 mg, 99% yield). The same reaction wasperformed using 1.5 equiv of 2 at rt for 18 h to give 5q (130.5 mg, 81%yield). Pentane was used as eluent for column chromatography. ¹H NMR(400 MHz, CDCl₃) δ: 7.75-7.62 (m, 6H), 7.52-7.42 (m, 3H). ¹³C{¹H} NMR(125 MHz, CDCl₃) δ: 144.9, 139.6, 129.0 (q, J_(C—F)=1.63 Hz), 128.3 (q,J_(C—F)=1.50 Hz), 127.6-127.3 (m), 118 (tq, J_(C—F)=34.3, 286 Hz), 115.4(tt, J_(C—F)=30.9, 254 Hz), 108.8 (tqt (apparently triplet of sextet),J_(C—F)=34.3, 30.9, 263 Hz). ¹⁹F NMR (376 MHz, CDCl₃) δ: −80.5 (triplet,3F, J=9.8 Hz), −112 (apparently quartet, 2F, J=9.8 Hz), −127 (apparentlysinglet, 2F). Anal. Calcd for C₁₅H₉F₇: C, 55.91; H, 2.82. Found: C,55.55; H, 2.62.

1-(Benzyloxy)-4-(perfluoropropyl)benzene (5r):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 2 at 50° C.for 18 h to give 5r (174.7 mg, 99% yield). Pentane was used as eluentfor column chromatography. ¹HNMR (400 MHz, CDCl₃) δ: 7.43-7.34 (m, 7H),7.08-7.06 (m, 2H), 5.11 (s, 2H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 161.5,136.1, 128.9-127.5 (m, 6C), 120.9 (t, J_(C—F)=24.8 Hz), 119.2 (tq,J_(C—F)=30.5, 286 Hz), 115.4 (tt, J_(C—F)=30.6, 253 Hz), 108.7 (tqt(apparently triplet of sextet), J_(C—F)=30.5, 30.6, 265 Hz). ¹⁹F NMR(376 MHz, CDCl₃) δ: −80.5 (triplet, 3F, J=8.7 Hz), −111 (apparentlyquartet, 2F, J=8.7 Hz), −127 (apparently singlet, 2F). Anal. Calcd forC₁₆H₁₁F₇O: C, 54.56; H, 3.15. Found: C, 54.20; H, 3.00.

1-Nitro-4-(perfluoropropyl)benzene (5j):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 2 at 50° C.for 18 h to give 5j (128.4 mg, 88% yield). Pentane was used as eluentfor column chromatography. ¹H NMR (500 MHz, CDCl₃) δ: 8.38 (d, 2H, J=9.0Hz), 7.81 (d, 2H, J=9.0 Hz). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 150.2,134.6 (t, J_(C—F)=23.9 Hz), 128.3 (t, J_(C—F)=6.3 Hz), 123.9, 117.8 (tq,J_(C—F)=33.6, 286 Hz), 114.5 (tt, J_(C—F)=31.3, 255 Hz), 108.5 (tqt(apparently triplet of sextet), J_(C—F)=33.6, 31.3, 264 Hz). ¹⁹F NMR(469 MHz, CDCl₃) δ: −80.4 (triplet, 3F, J=9.4 Hz), −113 (apparentlyquartet, 2F, J=9.4 Hz), −127 (apparently singlet, 2F). Anal. Calcd forC₉H₄F₇NO₂: C, 37.13; H, 1.38; N, 4.81. Found: C, 37.40; H, 1.66; N,4.86.

7-Chloro-4-(perfluoropropyl)quinoline (5x):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 2 at 50° C.for 18 h to give 5x (150.4 mg, 91% yield). The same reaction wasperformed using 1.5 equiv of 2 at rt for 18 h to give 5x (152.4 mg, 92%yield). In this substrate, different quenching method was used. Afterstirring 18 h, the mixture was poured into 29% aqueous ammoniumhydroxide solution (20 mL) and extracted with ether (20 mL×3). Then,organic phase was combined and dried over anhydrous NaSO₄ and filtrateand evaporate. The resultant was diluted with ether and wash 1 M HCl,sat. NaHCO₃ and brine, then dried over Na₂SO₄. After filtration andevaporation of the solvent, the crude mixture was purified by flashsilica gel column chromatography using pentane/Et₂O=5/1 to 2/1 as eluentto give ArCF₃₅x. ¹H NMR (500 MHz, CDCl₃) δ: 9.06 (d, 1H, J=4.0 Hz), 8.21(d, 1H, J=2.0 Hz), 8.09 (dd, 1H, J=2.0, 9.0 Hz), 7.64-7.59 (m, 2H).¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 150.3, 149.6, 136.3, 133.3 (t,J_(C—F)=23.0 Hz), 129.5, 129.4, 125.9 (septet, J_(C—F)=10.8 Hz), 122.5,120.9 (t, J_(C—F)=31.4 Hz), 117.8 (tq, J_(C—F)=33.6, 286 Hz), 115.9 (tt,J_(C—F)=32.9, 260 Hz), 108.9 (tqt (apparently triplet of sextet),J_(C—F)=33.6, 32.9, 264 Hz). ¹⁹F NMR (469 MHz, CDCl₃) δ: −80.4 (triplet,3F, J=9.85), −108 (apparently quartet, 2F, J=9.85), −125 (apparentlysinglet, 2F). Anal. Calcd for C₁₂H₅ClF7N: C, 43.46; H, 1.52; N, 4.22.Found: C, 43.58; H, 1.79; N, 4.17.

tert-Butyl 5-(perfluoropropyl)-1H-indole-1-carboxylate (5y):

Reaction was performed on 0.50 mmol scale using 1.5 equiv of 2 at 50° C.for 18 h to give 5y (177.5 mg, 92% yield). Pentane was used for columnchromatography. ¹H NMR (500 MHz, CDCl₃) δ: 8.27 (d, 1H, J=8.5 Hz), 7.81(s, 1H), 7.70 (d, 1H, J=3.5 Hz), 7.51 (d, 1H, J=8.5 Hz), 6.66 (d, 1H,J=3.5 Hz), 1.69 (s, 9H). ¹³C{¹H} NMR (125 MHz, CDCl₃) δ: 149.3, 136.9,130.3, 127.5, 122.8 (t, J_(C—F)=24.1 Hz), 122.2 (t, J_(C—F)=6.3 Hz),120.0 (t, J_(C—F)=6.9 Hz), 118.1 (tq, J_(C—F)=34.1, 286 Hz), 115.7 (tt,J_(C—F)=30.4, 254 Hz), 115.3, 108.8 (tqt (apparently triplet of sextet),J_(C—F)=34.1, 30.4, 262 Hz), 107.3, 84.5, 28.1. ¹⁹F NMR (469 MHz, CDCl₃)δ: −80.5 (triplet, 3F, J=9.4 Hz), −113 (apparently quartet, 2F, J=9.4Hz), −127 (apparently singlet, 2F). HRMS (EI): Calcd for C₉H₄F₇NO₂:385.0913. Found: 385.0930.

4-(n-Butyl)-1-(perfluoropropyl)benzene (5b):

To a 4-mL vial equipped with a stir bar were added(1,10-phenanthroline)(heptafluoropropyl)copper(I) (2) (14.4 mg, 0.035mmol) and 4-(trifluoromethoxy)anisole in DMF (0.70 mL, 0.050 M, 0.035mmol). To the mixture was added ArI 3b (31 μL, 0.18 mmol, 5.0 equiv),and the mixture was stirred at room temperature for 18 h. After thereaction, the mixture was transferred to an NMR tube, and the yield ofArCF₂CF₂CF₃ 5b was determined by ¹⁹F NMR analysis to be 84%.

Example 9 Generation of (phen)Cu—CF₂CF₂CF₃ in situ And SubsequentFluoroalkylation Reactions Using Aromatic Iodide (3) as Limiting Agent

General Procedure in Glove Box:

To a 20-mL vial equipped with a stir bar were added CuCl (99 mg, 1.0mmol, 2.0 equiv.), KOtBu (112 mg, 1.0 mmol, 2.0 equiv.) and1,10-phenanthroline (180 mg, 1.0 mmol, 2.0 equiv.), and DMF (2.0 mL) wasadded. The dark red mixture was stirred at room temperature for 30 minthen TMSCF₂CF₂CF₃ (0.203 mL, 1.0 mmol, 2.0 equiv.) was added dropwise.The resulting mixture was further stirred at room temperature for 1 hand then ArI 3q (0.50 mmol) was added. The resulting mixture was stirredat 80° C. for 18 h, then cooled, diluted with Et₂O and filtered througha pad of Celite. The Celite pad was washed with Et₂O and the combinedorganic layer was washed with 1M aqueous HCl, saturated aqueous NaHCO₃solution and brine, and dried over Na₂SO₄. After filtration andevaporation of the solvent, the crude mixture was purified by flashsilica gel column chromatography using pentane/Et₂O as eluent to giveArCF₂CF₂CF₃ 5q.

General Procedure for Conducting Reactions Outside of a Glove Box:

To a 20-mL vial equipped with a stir bar and a Teflon-lined screw capwas added CuCl (99 mg, 1.0 mmol, 2.0 equiv.) then air in the vial wasevacuated and dry nitrogen was refilled (once) and were added KOtBu (112mg, 1.0 mmol, 2.0 equiv.) and 1,10-phenanthroline (180 mg, 1.0 mmol, 2.0equiv.) then air in the vial was evacuated and dry nitrogen was refilled(twice). To the mixture was added DMF (2.0 mL), and the dark red mixturewas stirred at room temperature for 30 min under nitrogen thenTMSCF₂CF₂CF₃ (0.2013 mL, 1.0 mmol, 2.0 equiv.) was slowly added. Theresulting mixture was further stirred at room temperature for 1 h andthe stirring was stopped. Then the screw cap was removed and ArI 3q(0.50 mmol) was expeditiously added. While opening the cap, surface ofthe vial turned green, implying partial decomposition of the copperreagent. The cap of the vial was closed tightly and the vial wasevacuated and refilled with dry nitrogen. The resulting mixture wasstirred at 80° C. for 18 h, then cooled, diluted with Et₂O and filteredthrough a pad of Celite. The Celite pad was washed with Et₂O and thecombined organic layer was washed with 1M aqueous HCl, saturated aqueousNaHCO₃ solution and brine, and dried over Na₂SO₄. After filtration andevaporation of the solvent, the crude mixture was purified by flashsilica gel column chromatography using pentane/Et₂O as eluent to giveArCF₂CF₂CF₃₅q.

4-(Perfluoropropyl)biphenyl (5q):

Reaction was performed on 0.50 mmol scale using 2.0 equiv of CuCl,KOtBu, 1,10-phenanthroline and TMSCF₃ at 50° C. or 80° C. for 18 h inGlove Box to give 5q (50° C.: 92.3 mg, 57% yield 80° C.: 130.1 mg, 81%yield). The same reaction was performed at outside Glove Box using 2.0equiv of CuCl, KOtBu, 1,10-phenanthroline and TMSCF₃ at 80° C. for 18 hto give 5q (127.6 mg, 79% yield).

Example 10 Mechanistic Studies of Fluoroalkylation Reaction

To assess whether the reaction proceeds via radical intermediates, thetrifluoromethylation reaction was conducted with 2-(allyloxy)iodobenzene3ab. If the trifluoromethylation occurs through an aryl radical, thencyclized product 6 should be observed (FIG. 5). Instead, thetrifluoromethylarene 4ab was obtained in 91% yield, and the cyclizedproduct 6 was not detected by GC-MS analysis. This result implies thatthe copper-mediated trifluoromethylation reaction proceeds through anon-radical pathway.

To a 4-mL vial equipped with a stir bar were added(1,10-phenanthroline)(trifluoromethyl)copper(I) (1) (10.9 mg, 0.035mmol) and 4-(trifluoromethoxy)anisole in DMF (0.70 mL, 0.050 M, 0.035mmol). To the mixture was added 2-(allyloxy)iodobenzene 3ab (45.5 mg,0.175 mmol, 5.0 equiv), and the mixture was stirred at room temperaturefor 18 h. After the reaction, the mixture was transferred to an NMRtube, and the yield of 2-(allyloxy)(trifluoromethyl)benzene 4ab wasdetermined by ¹⁹F NMR analysis to be 91%. The mixture was also analyzedby GC-MS. Only 4ab (12.304 min; m/z=202) was observed and no cyclizedbyproduct 6 (11.902 min; m/z=134) was detected.

Example 11 Fluoroalkylation Reactions of Aromatic Bromides (7) Using(phen)Cu—CF₃ (1) as Limiting Agent

To a 4-mL vial equipped with a stir bar were added 1 (10.9 mg, 0.035mmol), ArBr 7 (if solid, 0.175 mmol, 5.0 equiv) and4-(trifluoromethoxy)anisole (internal standard for ¹⁹F NMR analysis) inDMF (0.70 mL, 0.050 M, 0.035 mmol). To the mixture was added ArBr 7 (ifliquid, 0.175 mmol, 5.0 equiv), and the mixture was stirred at 110° C.After 18 h, the stirring was stopped and cooled to room temperature, andthe reaction mixture was transferred to an NMR tube, and the yield ofthe product 8 was measured by ¹⁹F NMR analysis with the followingparameters after reduction of the sw (sweep width) to include bothstandard (−58.6 ppm) and product peaks: at =10 (s), d1=10 (s), pw90=15.5(ms), pw=15.5 (ms) and nt=4. Structures and yields for products 8j, 8a,8q, 8c, 8g, 8t, 8h, 8i and 8ac are shown in FIG. 6.

Example 12 Fluoroalkylation Reaction of Vinyl Halide Using (phen)Cu—CF₃(1) as Limiting Agent

To a 4-mL vial equipped with a stir bar were added 1 (10.9 mg, 0.035mmol) and 4-(trifluoromethoxy)-anisole (internal standard for ¹⁹F NMRanalysis) in DMF (0.70 mL, 0.050 M, 0.035 mmol). To this mixture wasadded (E)-n-Hexyl-CH═CHI (0.35 mmol, 10.0 equiv), and a precipitateformed immediately. The mixture was stirred at room temperature. After18 h, the stirring was stopped, and the reaction mixture was transferredto an NMR tube, and the yield of the product was measured by ¹⁹F NMRanalysis with the following parameters after reduction of the sw (sweepwidth) to include both standard (−58.6 ppm) and product peaks: at =10(s), d1=10 (s), pw90=15.5 (μs), pw=15.5 (μs) and nt=4. Yield of(E)-n-Hexyl-CH═CH(CF₃) was 99%.

Example 13 Formation of (1,10-Phenanthroline)(trifluoromethyl)copper(I)(1)

Copper mesityl was prepared according to Tsuda et al, J. Org. Chem.1981, 46, 192) as a dull yellow powder, and was dissolved in THF (0.3 M)to give a light yellow solution. To this solution, 1.0 equivalent ofanhydrous t-BuOH was added dropwise, and the resulting light yellowsolution was stirred at room temperature for 2 hours.1,10-Phenanthroline was dissolved in THF (0.3 M), and the resultingclear solution was added to the copper-containing mixture to give a verydark purple solution (0.15 M overall). If the copper mesityl hadinsufficient purity, a dark solid precipitated, which would require thereaction to be repeated with higher quality copper mesityl.

After stirring this dark solution for 30 minutes, TMSCF₃ was addedslowly with rapid stirring. A light brown/orange solid started toprecipitate during or shortly after the addition of TMSCF₃. Theresulting suspension was stirred at room temperature for 12 hours. Thesolid was collected, washed with ether until the eluent was clear, anddried to provide reagent 1. Reagent 1 was obtained as an air andmoisture-sensitive orange solid in 80-85% yield, and itscharacterization data was consistent with that of complex 1 of Example1.

While various embodiments of the invention have been described, it willbe apparent to those of ordinary skill in the art that other embodimentsand implementations are possible within the scope of the invention.Accordingly, the invention is not to be restricted except in light ofthe attached claims and their equivalents.

1. A method of forming a fluorinated molecular entity, comprising:reacting in a reaction mixture an aromatic halide comprising an aromaticgroup and a halogen substituent bonded to the aromatic group, copper, afluoroalkyl group, and a ligand comprising at least one group-V donorselected from the group consisting of phosphorus and nitrogen; where theoverall molar ratio of copper to aryl halide in the reaction mixture isfrom 0.2 to 3; and forming a fluoroalkylarene comprising the aromaticgroup and the fluoroalkyl group bonded to the aromatic group.
 2. Themethod of claim 1, where the at least one functional group is selectedfrom the group consisting of an ether group, a hydroxyl group, analdehyde group, a ketone group, an ester group, an amine group, an amidegroup, a cyano group, a nitro group, a bromide group, and a chloridegroup.
 3. The method of claim 1, where the aromatic group is an arylgroup or a heteroaryl group selected from a phenyl group, a biphenylgroup, a binaphthyl group, a pyridyl group, a quinolinyl group, apyrimidinyl group and an indolyl group.
 4. The method of claim 1, wherethe aromatic halide is an aromatic iodide or an aromatic bromide.
 5. Themethod of claim 1, where the fluoroalkyl group has the formula:—C_(x)H_((2x-y))F_(y) where x is from 1 to 12 and y is from 1 to (2x+1).6. The method of claim 8, where the fluoroalkyl group is selected fromthe group consisting of —CF₃, —CF₂CF₃, —CH₂CF₃, —CH₂CH₂F, —CF₂CF₂CF₃,—CH₂CF₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂F, —CH(CF₃)₂ and —CF(CF₃)₂.
 7. Themethod of claim 1, where the ligand is selected from the groupconsisting of a phenanthroline, an N,N′-disubstituted diamine, abipyridyl, a pyridyl, a phosphine, and a phosphite.
 8. The method ofclaim 1, where the ligand is selected from the group consisting of1,10-phenanthroline (phen), bipyridyl (bipy), pyridyl (Py),tetramethylenediamine (TMEDA), N,N′-dimethylethylenediamine (DMEDA),N,N′-dimethyl-cyclohexanediamine (DMECA), tributyl phosphine [(n-Bu)₃P],triphenyl phosphine (Ph₃P), trimethyl phosphite [(MeO)₃P] and triphenylphosphite [(PhO)₃P].
 9. The method of claim 1, where the ligand is1,10-phenanthroline.
 10. The method of claim 1, where the overall molarratio of copper to aryl iodide in the reaction mixture is from 0.95 to1.1.
 11. The method of claim 1, where the ligand comprises two pyridinylgroups, the fluoroalkyl group is —CF₃, and and the copper and thefluoroalkyl group are present in an overall molar ratio of approximately1 in the reaction mixture.
 12. The method of claim 11, where the ligandis 1,10-phenanthroline.
 13. The method of claim 1, where the ligand is1,10-phenanthroline, the fluoroalkyl group has the formula:—C_(x)H_((2x-y))F_(y) where x is from 1 to 12 and y is from 1 to (2x+1),and the copper and the fluoroalkyl group are present in an overall molarratio of approximately 1 in the reaction mixture.
 14. The method ofclaim 1, where the yield of fluoroalkylarene in the reaction mixture isat least 50%.
 15. The method of claim 1, where the reaction mixturefurther comprises a polar aprotic solvent.
 16. A composition, consistingessentially of: copper, a fluoroalkyl group, and a ligand comprising atleast one group-V donor; where the molar ratio of copper to thefluoroalkyl group is approximately
 1. 17. The composition of claim 16,where the fluoroalkyl group has the formula:—C_(x)H_((2x-y))F_(y) where x is from 1 to 12 and y is from 1 to (2x+1).18.-22. (canceled)
 23. A composition, consisting essentially of: copper,a fluoroalkyl group, a first ligand comprising at least one group-Vdonor, and a second ligand, different from the first ligand; where themolar ratio of copper to the fluoroalkyl group is approximately 1.24.-27. (canceled)
 28. A method of forming a fluorinated molecularentity, comprising: reacting in a reaction mixture; a vinyl halidecomprising an organic group containing a vinyl group and a halogensubstituent bonded to a carbon of the vinyl group, copper, a fluoroalkylgroup, and a ligand comprising at least one group-V donor selected fromthe group consisting of phosphorus, a ring nitrogen of a heterocyclicgroup, and a tertiary amine; where the overall molar ratio of copper tovinyl halide in the reaction mixture is from 0.2 to 3; and forming afluoroalkylvinyl compound comprising the organic group containing avinyl group and the fluoroalkyl group bonded to a carbon of the vinylgroup.
 29. A method of forming a copper-containing reagent, comprising:reacting in a reaction mixture, a copper source comprising acopper-carbon bond or a copper-nitrogen bond an alcohol, a compoundcomprising at least one group-V donor, and atri-organo(fluoroalkylsilane); and forming [(L)Cu—R_(f)] in the reactionmixture, where L is a ligand comprising at least one group-V donor, andR_(f) is a fluoroalkyl group. 30.-39. (canceled)